Effects of fenfluramine on free-operant timing behaviour: Evidence for involvement of 5-HT_2A receptors

Rationale: Temporal differentiation in the free-operant psychophysical procedure is sensitive to the 5-hydroxytryptamine (5-HT)_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and the 5-HT ₂ receptor agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI); both drugs shift the psychophysical curve leftwards, reducing the indifference point, T₅₀. We have examined the effect of the 5-HT releasing agent fenfluramine on temporal differentiation. Objective: We examined whether fenfluramine's effect on temporal differentiation can be antagonised by the 5-HT_1A receptor antagonist N-[2-(4-[2-methoxy-phenyl]-1-piperazinyl) ethyl]-N-2-pyridinylcyclohexane-carboxamide (WAY-100635) and the 5-HT _2A receptor antagonist ketanserin, and compared the effects of fenfluramine, DOI and 8-OH-DPAT in intact rats and rats whose 5-HTergic pathways had been destroyed by 5,7-dihydroxytryptamine. Methods: Rats were trained under the free-operant psychophysical procedure to press levers A and B in 50-s trials in which reinforcers were provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic psychophysical curves were fitted to the data for derivation of timing indices (T₅₀, time corresponding to %B=50%, and Weber fraction). Experiment 1 examined the effects of acute treatment with fenfluramine, and the interaction between fenfluramine and the 5-HT_1A and 5-HT_2A receptor antagonists WAY-100635 and ketanserin; experiment 2 compared the effects of fenfluramine, 8-OH-DPAT and DOI in intact rats and rats whose 5-HTergic pathways had been destroyed by intra-raphe injection of 5,7-dihydroxytryptamine. Concentrations of 5-HT and catecholamines in the brain were measured by high-performance liquid chromatography. Results: Experiment 1: fenfluramine (2 mg/kg) reduced T₅₀; this effect was attenuated by ketanserin (1.0 mg/kg) but not by WAY-10063 5 (100 μg/ kg). Experiment 2: 8-OH-DPAT (100 μg/kg) and DOI (250 μg/kg) reduced T₅₀ in both groups; fenfluramine reduced T₅₀ only in the sham-lesioned group. Levels of 5-HT were reduced by 80% in the lesioned group; catecholamine levels were not affected. Conclusions: The results suggest that fenfluramine affects temporal differentiation via the release of endogenous 5-HT which acts mainly on postsynaptic 5-HT_2A receptors.